Process for preparation of dronedarone by the use of dibutylaminopropanol reagent

ABSTRACT

The invention relates to a novel process for preparation of dronedarone of formula (I) and pharmaceutically acceptable salts thereof, characterized in that a compound of formula (II)—where L is leaving group—is reacted with compound of formula (III) and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

This invention relates to a novel process for the preparation ofdronedarone and pharmaceutically acceptable salts thereof, to novelintermediary compounds used in this process and their preparation.

TECHNICAL BACKGROUND

Dronedarone is a known drug for the treatment of arrhythmia and has thechemical name ofN-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran-5-yl]methanesulfon-amide[see also formula (I) below]. There are some known processes for thepreparation of dronedarone as follows:

In EP 0471609 the following scheme is disclosed for the preparation ofdronedarone [Process A]

The above mentioned patent description discloses some new intermediarycompounds, too.

In WO 02/48078 the following scheme is disclosed for the preparation ofdronedarone [Process B]:

The novelty of the process is based on the adaptation of theFriedel-Crafts reaction in the first step. The process and theintermediary compounds used for the preparation of the benzoylchloridecompound of the first step are also disclosed in this document. Thefurther steps of the process are identical with the final steps of thesynthetic route disclosed in EP 0471609 [Process A], but in the claimsthe whole synthetic route is claimed, up to dronedarone.

In WO 02/48132 (Sanofi) the following reaction route is disclosed[Process C]. This method is the so called superconvergent route. In thefirst step of it 5-amino-2-butyl-benzofuran

is mesylated and the obtained 2-butyl-5-methanesulfonamido-benzofuran(in HCl salt form) is further reacted in the next step as follows:

In this process the order of reaction steps are altered, the reductionand the methansulfonylation steps are performed at the beginning of theprocedure. Besides the reaction route for preparation of dronedarone,the starting material 2-butyl-5-methansulfonamido-benzofuran and itspreparation is also claimed.

From among the mentioned procedures the first one [Process A] is the socalled linear synthesis. In this way of procedure the different parts ofthe dronedarone are stepwise built up on the starting compound. Thismethod is the least economical because the step by step building of thechemical groups is performed where more and more complicated andexpensive molecules are applied which rises the costs of preparation.Furthermore, it comprises complicated and dangerous reaction stepbecause aluminium chloride is used in the cleaving reaction of themethoxy group which makes the industrial feasibility more complicated.

In WO 02/48078 (Process B) a shorter synthetic route is disclosed whichmakes this process more economical, but its last reaction step remainedthe methansulfonylation reaction of the amino group. This reaction step(see the method described in example 6 of of WO 02/48078) is complicatedand give a low yield, only 61.6%. Pure product can be obtained afterpurification using chromatographic column purification, which method isnecessary because of the separation difficulties of thebis-methanesulfonylated product.

The process disclosed in WO 02/48132 (process C) is simpler and moreeconomical taken into consideration the number of the reaction steps.Unfortunately, in the last reaction step rather impure dronedarone.HCl(hydrochloride) is formed which is the obvious consequence of thepresence of dibutylamino group in the Friedel-Crafts reaction. Accordingto Examples 3 and 4, the crude dronedarone hydrochloride salt isprepared with a yield of 90% which was further purified and finally thecrude dronedarone base was produced with a yield of 86%. This base isreacted with hydrogen chloride gas dissolved in isopropanol whichresults in pure dronedarone hydrochloride salt. No yield was given forthis reaction step. According to example 5 crude dronedaronehydrochloride salt was prepared with a yield of 90%, which was washedwith water and reacted with hydrogen chloride gas dissolved inisopropanol, resulting dronedarone hydrochloride salt again. The qualityof this product is not known. However, neither the components used inthe Friedel-Crafts reaction nor the resulted products and by-productsare soluble in water, the washing step with water cannot result anypurification apart from the removal of inorganic salts.

It is an object of present invention to provide a novel process for thepreparation of dronedarone of formula (I). Starting with known andcommercially available materials, applying simple and environmentallycompatible reagents and solvents to afford high overall yields and goodpurity of the product.

SUMMARY OF THE INVENTION

The main aspect of the invention is a process for preparation ofdronedarone (I) and pharmaceutically acceptable salts thereof

wherein the compound of formula (II)

-   -   where L is leaving group—is reacted with compound of formula        (III)

and the obtained product is isolated and, if desired, converted into apharmaceutically acceptable salt thereof.

This new procedure avoids the drawbacks of the procedures mentionedbefore, because the intermediates are easily to prepare and the startingmaterials are not expensive to purchase. In the final step thedibutylamino-ethanol can be removed from the other components easily andthe other by-products can be removed very effectively usingchromatographic purification or salt forming. In the final reaction usedcompounds of formula (II) are new and can be prepared using knownmethods (Yakugaku Zasshi (1956) 76, 637-40; J. Am. Chem. Soc. vol 104.No 11.3173; Synthesis (1981), 155.)

The starting compound of structure (VIII) is known [EP 0471 609,Sanofi]. Some intermediary compounds used in synthesis of dronedaroneare new. Dibutylamino-propanol is known in the literature and can beprepared according to the process described in Journal of the AmericanChemical Society 1946, (7), 1297-99. Further aspects of the inventionare the novel intermediary compounds and the methods for the preparationthereof (see below in the “Detailed description of the invention” part).The applied other starting materials are available from commercialsources.

DETAILED DESCRIPTION OF THE INVENTION

Therefore the present invention relates to a process for the preparationof dronedarone and pharmaceutically acceptable salts thereof. The wholeprocess—starting from compounds available commercial sources—reads asfollows:

A) For the preparation of compound of formula (VII)

the compound of formula (VIII)

is reacted with activated form of a compound of HO—SO₂-L″ (IX),

where L″ is leaving group, for example alkyl (e.g. methyl), halogenatedalkyl (e.g. trifluoromethyl), aryl (e.g. phenyl), optionally substitutedwith halogen, alkyl, alkoxy or nitro group.

The “activated form” of compound (IX) is for example a halogenidederivative thereof (OH changed for halogen) or anhydride form ofcompound (IX).

The reaction is carried typically in a solvent, which can be e.g.dichloromethane, dichloroethane, chlorobenzene or mixtures thereof.

B) For the preparation of compound of formula (VI) and pharmaceuticallyacceptable salts thereof

a compound of formula (VII)

is hydrogenated, where L′ and L″ is a leaving group, and the obtainedproduct is isolated and, if desired, converted into a pharmaceuticallyacceptable salt thereof.

The meaning of L′ can be selected from the following group: halogen,alkylsulfonyloxy, optionally substituted with one or more halogen (e.g.methanesulfonyloxy, trifluoromethanesulfonyloxy) and arylsulfonyloxy(e.g. benzenesulfonyloxy), optionally substituted with halogen, alkyl,alkoxy or amino.

The meaning of L″ can be selected from the following group: halogen,alkylsulfonyloxy, optionally substituted with one or more halogen (e.g.methanesulfonyloxy, trifluoromethanesulfonyloxy) and arylsulfonyloxy(e.g. benzenesulfonyloxy), optionally substituted with halogen, alkyl,alkoxy or nitro.

The hydrogenation of compound of formula (VII) is carried out in asolvent or mixture of solvents, in the presence of a catalyst, which canbe e.g. PtO₂ or Pd/C. The solvent can be selected from the group C1-C4alcohols, ethyl acetate, cyclohexane and tetrahydrofurane and mixturesthereof (e.g. ethanol or methanol).

C) For the preparation of compound of formula (II) and pharmaceuticallyacceptable salts thereof

where L is a leaving group, typically halogen, alkylsulfonyloxy,optionally substituted with one or more halogen (e.g.methanesulfonyloxy, trifluoromethanesulfonyloxy) or arylsulfonyloxy(e.g. benzenesulfonyloxy), optionally substituted with halogen, alky,alkoxy or alkylsulfonylamino (e.g. methanesulfonylamino),

a) when L is halogen, then the compound of formula (IV)

is reacted with a compound of formula (V)

where Hal is halogen, and

b) when L is different from halogen, e.g. alkylsulfonyloxy, optionallysubstituted with one or more halogen (e.g. methanesulfonyloxy,trifluoromethanesulfonyloxy) or arylsulfonyloxy (e.g.benzenesulfonyloxy), optionally substituted with halogen, alky, alkoxyor alkylsulfonylamino (e.g. methanesulfonylamino), then a compound offormula (VI)

where L′ is alkylsulfonyloxy, optionally substituted with one or morehalogen (e.g. methanesulfonyloxy, trifluoromethanesulfonyloxy) orarylsulfonyloxy (e.g. benzenesulfonyloxy), optionally substituted withhalogen, alky, alkoxy or amino, is mesylated,

and the obtained product is isolated and, if desired, converted into apharmaceutically acceptable salt thereof.

In process variant a) the reaction is carried out under Friedel-Craftreaction conditions (see e.g. in Advanced Organic Chemistry John Wileyand Sons 4. Ed. 1992, 538-42).

The reaction is carried out in halogenated and nitro group containingsolvents, e.g. dichloromethane, dichloroethane, chlorobenzene,nitromethane, nitrobenzene. Catalyst also can be applied, typicallyLewis acids, e.g. AlCl₃, FeCl₃, SnCl₄, TiCl₄.

In process variant b) the mesylation is carried out in a solvent ormixture of inert solvents, typically in the presence of base. Thesolvent can be selected from the group of halogenated solvents (e.g.dichloromethane, dichloroethane, chlorobenzene), aromatic solvents (e.g.toluene) and ethers (e.g. diisopropyl ether) and mixtures thereof. Thebase can be selected from group of tercier amines (e.g. pyridine ortriethyl amine) and inorganic bases (e.g. carbonates, hydrogencarbonates, alkali hydroxides).

In the process a mesylating reagent should be applied. It can be anyreagent which can be used for inserting a CH₃SO₂—group into the freeamino group of compound of formula (VI). It is practical to usemethanesulfonic anhydride or methanesulfonyl halogenide, e.g.methanesulfonyl chloride.

D) Finally, for the preparation of dronedarone of formula (I) andpharmaceutically acceptable salts thereof

an above compound of formula (II) [where L is leaving group, typicallyselected from the group of halogen, alkylsulfonyloxy, optionallysubstituted with one or more halogen (e.g. methanesulfonyloxy,trifluoromethanesulfonyloxy), and arylsulfonyloxy (e.gbenzenesulfonyloxy), optionally substituted with halogen, alky, alkoxyor alkylsulfonylamino (e.g. methanesulfonylamino), is reacted withcompound of formula (III)

and the obtained product is isolated and, if desired, converted into apharmaceutically acceptable salt thereof.

Typically the reaction is carried out in solvents in presence of base,optionally in the presence of a catalyst.

The solvent can be e.g. dimethyl formamide, dimethyl sulfoxide,hexamethylphosphoramide, mono- or dialkyl pyridine and similar polarsolvents and any mixtures thereof.

In some cases an alkali salt of the compound of formula (III) is used asbase.

The catalyst may be for example a copper salt (e.g. copper iodide) orcopper oxide catalyst, when L leaving group is halogen. When L isdifferent from halogen, then there is no necessity to use catalyst.

Typically the reaction is carried out in the presence of a base, whichcan be selected from the group of (alkaline hydroxide, alkaline hydride,alkaline amide, e.g. KOH, NaH, Na-amide.

As used herein, the term alkyl includes straight or branched aliphatichydrocarbon chains of 1 to 6 carbon atoms, e.g., methyl, ethyl,isopropyl and t-butyl.

As used herein, the term “aryl” includes aromatic monocyclic ormulticyclic ring systems comprising 6 to about 14 carbon atoms,preferably 6 to about 10 carbon atoms. Non-limiting examples of suitablearyl groups include phenyl and naphthyl.

As used herein, the term, halogen” includes fluoro, chloro, bromo andiodo atoms.

In the above reactions the temperature is chosen according to thegeneral practice of a person skilled in organic chemistry. Typically thetemperature is between 10° C. and the boiling point of the appliedsolvent (which can be the mixture of the mentioned solvents in aspecific embodiment). Applicable temperature values can be found in theexamples.

All the above reactions are carried out under atmospheric pressure withthe exception of the hydrogenation steps where higher pressure also canbe applied, typically up to 20 bar, e.g. 5 to 10 bar.

The applicable acid for the preparation of pharmaceutically acceptablesalts can be any inorganic or organic acid which forms an acid additionsalt with the compound of general formula (I). Exemplary acids which canform an acid addition salt are as follows: acetic acid, adipic acid,alginic acid, ascorbic acid, aspartic acid, benzoic acid,benzenesulfonic acid, methansulfonic acid, ethansulfonic acid, boricacid, butyric acid, citric acid, ethanesulfonic acid, fumaric acid,hydrogen chloride, hydrogen bromide, hydrogen iodide,2-hydroxyethanesulfonic acid, maleic acid, oxalic acid, methanesulfonicacid, nitric acid, salicylic acid, tartaric acid, sulfuric acid (formingsulfate or bisulfate anion), sulfonic acid (such as those mentionedherein), succinic acid, toluenesulfonic acid and the like. The hydrogenhalogenide salts are typical, especially the hydrogen chloride salt.

Here it is mentioned that on the mesylate group of compound of generalformula (I) (see the “left side” of the molecules) a salt formation canbe carried out (on the amide part of it) by a strong base, e.g. analkaline hydroxide, typically by sodium hydroxide. However, these saltshave less practical importance, but they are within the scope of salts.It means that the phrase “salts” embraces both the acid addition saltsand the salts formed by bases (basic salts) in case of compounds ofgeneral formula (I).

As it was mentioned above the further starting materials arecommercially available or can be prepared by applying known syntheticways, e.g. as it is given in the relating examples.

Other objects of the invention are the novel intermediary compoundsapplied in the processes, namely the following compounds:

-   -   Compounds of formula (II) and pharmaceutically acceptable salts        thereof

where L is a leaving group selected from halogen, alkylsulfonyloxy,optionally substituted with one or more halogen, or arylsulfonyloxy,optionally substituted with halogen, alky, alkoxy or alkylsulfonylamino.

In a preferred embodiment the compound of formula (H) is selected fromthe following group:

-   -   Compounds of formula (VI) and pharmaceutically acceptable salts        thereof

where L′ alkylsulfonyloxy, optionally substituted with one or morehalogen, or arylsulfonyloxy, optionally substituted with halogen, alky,alkoxy or amino.

In a preferred embodiment the compound of formula (VI) is selected fromthe following group:

where L″ is alkylsulfonyloxy, optionally substituted with one or morehalogen, or arylsulfonyloxy, optionally substituted with halogen, alky,alkoxy or nitro.

In a preferred embodiment the compound of formula (VII) is selected fromthe following group:

Other objects of the invention are the processes for the preparation ofthe novel intermediary compounds, namely the following ones:

-   -   Process for preparation of compounds of formula (II) and        pharmaceutically acceptable salts thereof

where L is leaving group, characterized in that

a) when L is halogen, then the compound of formula (IV)

is reacted with a compound of formula (V)

where Hal is halogen, and

b) when L is different from halogen, then a compound of formula (VI)

is mesylated, where L′ is a leaving group being different from halogen,

and the obtained product is isolated and, if desired, converted into apharmaceutically acceptable salt thereof.

-   -   Process for preparation of compounds of formula (VI) and        pharmaceutically acceptable salts thereof

where a compound of formula (VII)

is hydrogenated, where L″ is a leaving group,

and the obtained product is isolated and, if desired, converted into apharmaceutically acceptable salt thereof.

-   -   Process for preparation of compound of formula (VII)

characterized in that the compound of formula (VIII)

is reacted with activated form of a compound of HO—SO₂-L″ (IX),

where L″ is leaving group.

In the processes for the preparation of the intermediary compounds theproduct is isolated as a base typically (if the compound has analkylated amino group). If desired, the isolated base can be convertedinto a salt (acid addition salt) thereof, which is typically apharmaceutically acceptable salt [the possible acids are mentioned inpoint D)]. Theoretically the acid addition salt can be prepared directlyif the relating acid is in the final reaction mixture from which thesolid product is made (however, this way is not applied in case of thesecompounds where the base type form has practical importance).

Here it is mentioned that some of the above intermediary compounds havea mesylate group (see the “left side” of the molecules) where a saltformation can be carried out (on the amide part of it) by a strong base,e.g. an alkaline hydroxide, typically by sodium hydroxide. However,these salts have less practical importance, but they are within thescope of salts which can be prepared by the claimed process, i.e. thephrase “salts” embraces the salts formed by bases (basic salts) in suchcases (where the molecule has a mesylate group).

EXAMPLES Example 1N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide(I)

2 g ofN[2-butyl-3-(4-fluorobenzoyl)-1-benzofuran-5-yl])methanesulfonamide(2d), 1.0 g of powered Cut was added to a solution of 1.1 g ofdibutylamino-propanol sodium salt dissolved in 5 ml ofdimethylformamide. The mixture was stirred at 90-100° C. for 25 hours.After cooling the solution was filtered. The dimethylformamide wasevaporated in reduced pressure. 10 ml of water was added and the mixturewas extracted with 10 ml of dichloromethane. The dichloromethane phasewas washed at first with 10 ml of sodium carbonate of 5% then with 2×10ml of water and evaporated. The product was purified by columnchromatography on silica gel (eluent: ethyl acetate/hexane 1:3).

Mass of product: 2.86 g (100%).

Purity (HPLC): 99.5%.

¹H NMR(DMSO): 0.8-0.9 (m, 9H); 1.2-1.5 (m, 10H); 1.67 (5′, 2H); 1.87(5′, 2H); 2.38 (t, J=7.2 Hz, 4H); 2.57 (m, 2H); 2.81 (t, J=7.5 Hz, 2H);29.91 (s, 3H); 4.15 (t, J=6.2 Hz, 2H); 7.09 (d, J=8.8 Hz, 2H); 7.24 (dd,J=8.9, 2.2 Hz, 1H); 7.34 (d, H=2.1 Hz, 1H); 7.65 (d, J=8.8 Hz, 1H); 7.81(d, J=8.8 Hz, 2H).

Example 2N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide(I)

1.7 g ofN-[2-butyl-3-(4-chlorobenzoyl)-1-benzofuran-5-yl])methanesulfonamide(2a), 0.8 g of powered CuI was added to a solution of 1.05 g ofdibutylamino-propanol sodium salt dissolved in 8 ml of collidine. Themixture was stirred at 100° C. for 10 hours. After cooling the solutionwas filtered and the reaction mixture was evaporated in reducedpressure. 10 ml of water was added and the mixture was extracted with 10ml of dichloromethane. The dichloromethane phase was washed with 10 mlof sodium carbonate of 5% and with 2×10 ml of water. After drying thedichloromethane was evaporated.

Mass of product: 2.25 g (96.1%). The product was identical with thecompound prepared in Example 1.

Example 3N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}benzofuran-5-yl]-methanesulfonamide(I)

2.1 g ofN-[2-butyl-3-(4-iodobenzoyl)-1-benzofuran-5-yl])methanesulfonamide (2c)and 1.14 g of dibutylamino-propanol potassium salt was dissolved in 10ml of dimethyl-sulfoxide. The mixture was stirred for 30 minutes at 130°C. After cooling to the mixture 15 ml of water was added and extractedwith 2×10 ml of dichloromethane. After drying the dichloromethane wasevapored and purified using column chromatography on silica gel (eluent:ethyl acetate/hexane 1:3).

Mass of product: 2.1 g (89.7%). The product was identical with thecompound prepared in Example 1.

Example 4N-[2-butyl-3-{4-[(3-dibuylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide(I)

2.7 ofN-[2-butyl-3-(4-bromobenzoyl)-1-benzofuran-5-yl])methanesulfonamide (2b)and 1.36 of dibutylamino-propanol potassium salt was dissolved in 25 mlof hexamethylphosphor-amide and the reaction mixture was stirred et 90°C. for 20 hours. The mixture was cooled, 50 ml of water was added andthe mixture was extracted with 2×20 ml of dichloromethane. Thedichloromethane was evaporated after drying and purified using columnchromatography on silica gel (eluent: ethyl acetate/hexane 1:3).

Mass of product: 3.25 g (97.4%)

The product was identical with compound prepared in Example 1.

Example 5N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide(I)

2.4 g of4-({2-butyl-5-[(methylsulfonyl)amino]-benzofuran-3-yl}carbonyl)phenyl-trifluoro-methanesulfonate(2g) was dissolved in the solution of 0.33 g of potassium hydroxide of85% in abs. dimethylformamide. After complete dissolution 0.98 g ofdibutylamino-propanol was added and the mixture was stirred at 40° C.for 9 hours and cooled down. The solvent was evaporated and the residuewas dissolved in 15 ml of dichloromethane. 10 ml of water was added andthe mixture was stirred for 5 minutes. The phases were separated. Thedichloromethane was washed with 2×10 ml of water and after dryingevaporated and purified using column chromatography on silica gel(eluent: ethyl acetate/hexane 1:3).

Mass of product: 2.67 g (93.6%). The product was identical with compoundprepared in Example 1.

Example 6N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide(I)

3 g of4-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-methyl-benzenesulfonate(2h) was added to a dispersion prepared from 0.3 g of sodium hydride of50% dispersed in 10 ml of dimethylformamide. 1.1 g ofdibutylamino-propanol was added and the mixture was stirred at 25° C.for 10 hours. The dimethylformamide was evaporated in reduced pressure.12 ml of water was added and the mixture was extracted with 2×10 ml ofdichloromethane. The dichloromethane was washed with 10 ml of sodiumcarbonate of 5% and with 2×10 ml of water. The solvent was evaporatedand purified using column chromatography on silica gel (eluent: ethylacetate/hexane 1:3).

Mass of product: 2.78 g (92.7%). The product was identical with compoundprepared in example 1.

Example 7N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide(I)

The process according to example 5 was performed with the different thatin the reaction 3.2 g of4-({2-butyl-5-[methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-[(methyl-sulfonyl)amino]benzenesulfonate(2e) was used as reactant. The product was purified by columnchromatography on silica gel (eluent: ethyl acetate/hexane 1:3).

Mass of product: 3.67 g (96.5%). The product was identical with compoundprepared in Example 1.

Example 8N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide(I)

The process according to example 6 was performed with the differencethat in the reaction 3.1 g of4-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-chloro-benzenesulfonate(2f) was used as reactant. The product was purified by columnchromatography on silica gel (eluent: ethyl acetate/hexane 1:3).

Mass of product: 2.67 g (89.6%). The purified product was identical withcompound prepared in Example 1.

Example 9N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide(I)

The process according example 6 was performed with the difference thatin the reaction 2.7 g of4-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-methanesulfo-nate(2i) was used as reactant. The product was purified by columnchromatography on silica gel (eluent: ethyl acetate/hexane 1:3).

Mass of product: 2.05 g (89.1%). The product was identical with compoundprepared in example 1.

Example 10N-[2-butyl-3-(4-fluorobenzoyl)-1-benzofuran-5-yl]methanesulfonamide (2d)

3.64 g of 4-fluorobenzoyl-chloride—prepared by reacting 4-fluorbenzoicacid with thionyl chloride—and 5.42 g of2-butyl-5-methanesulfonylamido-benzofuran (IV) were dissolved in 30 mlof dichloromethane. The solution was cooled to 0 to 5° C. and at thistemperature 3.9 g ferrichloride was added in four portions in 20minutes. The mixture was allowed to warm to room temperature and wasstirred at this temperature for four hours. The mixture was warmed to40° C. and 54 ml of warm water (temperature: apprx. 30-35° C.) was addedin 30 minutes. After separation of phases the dichloromethane phase waswashed at 40° C. with 16 ml of water, 2×16 ml of sodium hydrocarbonateof 5% and with 2×16 ml of water.

The dichlorometane was evaporated. Mass of product: 6.7 g (89.9%).

This crude product was crystallized in hot isopropanol.

Mass of pure product: 3.19 g (HPLC: 100%). Mp: 151.0-151.9° C.

1H NMR(DMSO): 9.60 (s, 1H); 7.86 (dd, J=8.1, 5.8 Hz, 2H); 7.63 (d, J=8.8Hz, 1H); 7.39 (t, J=8.7 Hz, 2H); 7.26 (d, J=5.1 Hz, 1H); 7.21 (dd,J=8.8, 1.8 Hz, 1H); 2.88 (s, 3H); 2.79 (t, J=7.5 Hz, 2H); 1.65 (5′,J=7.3 Hz, 2H); 1.24 (6′, J=7.3 Hz, 2H); 0.80 (t, J=7.3 Hz, 3H).

Example 11N-[2-butyl-3-(4-iodobenzoyl)-1-benzofuran-5-yl]methanesulfonamide (2c)

6.12 g of 4-iodobenzoyl chloride—prepared by reacting 4-iodobenzoic acidwith thionyl chloride—and 5.42 g of2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml ofdichloromethane. The reaction was performed according to Example 10.

Mass of crude product: 8.65 g (85.8%).

The crude product was crystallized in hot isopropanol.

Mass of pure product: 5.53 g. Purity (HPLC): 100%. Mp: 189.1-190.1° C.

1H NMR(DMSO): 9.61 (s, 1H); 7.95 (d, J=8.6 Hz, 2H); 7.63 (d, J=8.8 Hz,1H); 7.54 (d, J=8.2, 2H); 7.28 (d, J=1.5 Hz, 1H); 7.22 (dd, J=8.8, 1.8Hz, 1H); 2.88 (s, 3H); 2.78 (t, J=7.5 Hz, 2H); 1.64 (5′, J=7.4 Hz, 2H);1.23 (6′, J=7.4 Hz, 2H); 0.80 (t, J=7.4 Hz, 3H)

Example 12N-[2-butyl-3-(4-bromobenzoyl)-1-benzofuran-5-yl]methanesulfonamide (2b)

5.08 g of 4-bromobenzoyl chloride—prepared by reacting 4-bromobenzoicacid with thionyl chloride—and 5.42 g of2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml ofdichloromethane. The reaction was performed according to Example 10.

Mass of crude product: 8.39 g (91.8%).

The crude product was crystallized in hot isopropanol.

Mass of pure product: 5.87 g (HPLC: 100%) Mp: 164.5-165.6° C.

1H NMR(DMSO): 9.61 (s,1H); 7.78 (d, J=8.4 Hz, 2H); 7.71 (d, J=8.4 Hz,2H); 7.64 (d, J=8.7 Hz, 1H); 7.27 (d, J=2.4 Hz, 1H); 7.22 (dd, J=2.1,8.7 Hz, 1H); 2.88 (s, 3H); 2.79 (t, J=7.4 Hz, 2H); 1.65 (5′, J=7.5 Hz,2H); 1.24 (6′, J=7.4 Hz, 2H); 0.80 (t, J=7.4 Hz, 3H)

Example 13N-[2-butyl-3-(4-chlorobenzoyl)-1-benzofuran-5-yl]methanesulfonamide (2a)

4.02 g of 4-chlorobenzoyl chloride—prepared by reacting 4-chlorobenzoicacid with thionyl chloride—and 5.42 g of2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml ofdichloromethane. The reaction was performed according to Example 10.

Mass of crude product: 8.16 g (99.3%).

The crude product was crystallized in hot isopropanol.

Mass of pure product: 4.2 g, (HPLC: 100%) Mp: 151.6-153.2° C.

1H NMR(DMSO): 9.61 (s, 1H); 7.79 (d, J=8.5 Hz, 2H); 7.63 (d, J=8.4 Hz,3H); 7.27 (d, J=2.1 Hz, 1H); 7.22 (d.d, J=2.2, 8.8 Hz, 1H); 2.88 (s,3H); 2.79 (t, J=7.5 Hz, 2H); 1.65 (5′, J=7.6 Hz, 2H); 1.24 (6′, J=7.4Hz, 2H); 0.81 (t, J=7.4 Hz, 3H)

Example 144-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyltrifluoromethanesulfonate(7g)

5.0 g of (2-butyl-5-nitro-3-benzofuranyl)(4-hydroxyphenyl)methanon(VIII) was dissolved in 50 ml of dichloromethane and 2.24 g oftriethylamine was added under cooling at 20° C. 4.75 g oftrifluoromethanesulfonyl anhydride was added in 30 minutes under gentlecooling. The mixture was boiled for 5 hours. After cooling to roomtemperature the mixture was stirred with 10 ml of sodium carbonate of10% for 2 hours and the phases were separated. The dichloromethane phasewas evaporated.

Mass of residual oil: 7.59 g (109%). The yield is over 100% because ofthe solvent content of the obtained oil.

Purity (HPLC): 94.9%.

1H NMR(DMSO): 8.30 (d, J=2.3 Hz, 1H); 8.28 (dd, J=8.9, 2.4 Hz, 1H); 8.00(d, J=8.8 Hz, 1H); 7.95 (d, J=9.0 Hz, 1H); 7.74 (d, J=8.8 Hz, 2H); 2.76(t, J=7.6 Hz, 2H); 1.66 (5′, J=7.7 Hz, 2H); 1.22 (6′, J=7.3 Hz, 2H);0.79 (t, J=7.3 Hz, 3H).

Example 154-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyltrifluoromethanesulfonate(6g)

7.59 g of4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyltrifluoro-methanesulfonate(7g) was dissolved in 80 ml of ethanol. 0.9 g of Pd/C of 10% was addedand the mixture was stirred at 75° C. under hydrogen pressure of 10 barsfor 6.5 hours. After cooling the catalyst was filtered off and thesolvent was evaporated.

Mass of product: 6.8 g (95.8%). Purity (HPLC): 94.1%.

1H NMR(DMSO): 7.91 (d, H=8.7 Hz, 2H); 7.70 (d, J=8.7 Hz, 2H); 7.28 (d,J=8.7 Hz, 1H); 6.60 (m, 2H); 5.0 (w, 2H); 2.62 (t, J=7.6 Hz, 2H); 1.59(5′, J=7.5 Hz, 2H); 1.2 (m, 2H); 0.78 (t, J=7.4 Hz, 3H).

Example 164-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-trifluoromethanesulfonate (2g)

6.6 g of4-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyltrifluoro-methanesulfonate(6 g) was dissolved in 65 ml of dichloromethane. The mixture was warmedto 30 to 35° C. and 1.3 g of pyridine was added at this temperature in 5minutes. 1.89 g of methanesulfonyl chloride was added at thistemperature in 30 minutes and the mixture was stirred at thistemperature for 4 hours. After cooling to 20° C. the mixture was washedwith 13 ml of water, 13 ml of HCl of 2.5%, with 13 ml of water, 13 ml ofsodium bicarbonate of 5% and with 13 ml of water. The dichlorometanephase was evaporated.

Mass of crude product: 7.2 g (92.8%).

The product was crystallized in hot isopropanol.

Mass of pure product: 5.41 g. Purity (HPLC): 96.5%. Mp: 143.3-144.1° C.

1H NMR(DMSO): 9.63 (s, 1H); 7.95 (d, J=8.8 Hz, 2H); 7.70 (d, J=8.7 Hz,2H); 7.64 (d, J=8.8 Hz, 1H); 7.35 (d, J=2.1 Hz, 1H); 7.22 (dd, J=8.8,2.2 Hz, 1H); 2.88 (s, 3H); 2.72 (t, J=7.5 Hz, 2H); 1.63 (5′, J=7.7 Hz,2H); 1.21 (6′, J=7.4 Hz, 2H); 0.79 (t, 7.6 Hz, 3H).

Example 174-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-4-nitrobenzenesulfonate(7e)

20 g of (2-butyl-5-nitro-3-benzofuranyl)(4-hydroxyphenyl)methanon (VIII)was dissolved in 200 ml of dichloromethane and 8.95 g of triethylaminewas added in 5 minutes at 20° C. 19.6 g of 4-nitrobenzenesulfonylchloride was added at 20° C. in 30 minutes under gentle cooling. Themixture was boiled for 5 hours. After cooling to room temperature themixture was stirred with 50 ml of sodium carbonate of 10% for 5 hours.Phase separation. The dichloromethane phase was evaporated.

Mass of residual oil: 37.62 g (121.7%). The yield is over 100% becauseof the solvent content of the obtained oil.

Purity (HPLC): 86.9%.

1H NMR(DMSO): 8.46 (d, J=8.8 Hz, 2H); 8.26 (dd, J=9.0, 2.3 Hz, 1H); 8.21(m, 3H); 7.93 (d, J=9.0 Hz, 1H); 7.85 (d, J=8.8 Hz, 2H); 7.32 (d, J=8.6Hz, 2H); 2.74 (t, J=7.6 Hz, 2H); 1.64 (5′, J=7.4 Hz, 2H); 1.20 (6′,J=7.5 Hz, 2H); 0.78 (t, J=7.5 Hz, 3H)

Example 184-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-4-aminobenzenesulfonate(6e)

37.44 g of4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-4-nitrobenzene-sulfonate(7e) was dissolved in 380 ml of ethanol. 4.1 g of Pd/C of 10% was addedand the mixture was stirred at 75° C. for 7 hours under hydrogenpressure of 10 bars. After cooling the catalyst was filtered off and thesolvent evaporated.

Mass of product: 31.7 g (96%).

Purity (HPLC): 94.4%.

1H NMP(DMSO): 7.73 (d, J=8.6 Hz, 2H); 7.45 (d, J=8.8 Hz, 2H); 7.27 (d,J=9.4 Hz, 1H); 7.17 (d, J=8.6 Hz, 2H); 6.63 (d, J=8.8 Hz, 2H); 6.59 (m,2H); 6.43 (w, 2H); 5.05 (w, 2H); 2.60 (t, J=7.5 Hz, 2H); 1.58 (5′, J=7.3Hz, 2H); 1.18 (m, 2H); 0.78 (t, J=7.3 Hz, 3H).

Example 194-({2-butyl-5-[methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-[(methylsulfonyl)-amino]benzenesulfonate(2e)

4 g of4-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-4-aminobenzene-sulfonate(6e) was dissolved in 40 ml of dichloromethane. The mixture was warmedto 30 to 35° C. and 1.5 g of pyridine was added at this temperature in 5minutes. 40 g of methansulfonyl chloride was added at this temperaturein 30 minutes and the mixture was stirred for 4.5 hours. After coolingto 20° C. the mixture was washed with 2×80 ml of water, 1×80 ml ofsodium bicarbonate of 5% and with 80 ml of water. The phases wereseparated. The dichloromethane phase was evaporated.

Mass of product: 1.91 g (34%).

Purity (HPLC): 83.3%. M.p.: 91.8-92.7° C.

1H NMR(DMSO): 10.7 (w, 1H); 9.62 (s, 1H); 7.86 (d, J=8.6 Hz, 2H); 7.80(d, J=8.6 Hz, 2H); 7.63 (d, J=8.7 Hz, 1H); 7.39 (d, J=8.9 Hz, 2H); 7.33(d, J=1.9 Hz, 1H); 7.23 (d, J=8.6 Hz, 2H); 7.21 (dd, J=8.9, 2.1 Hz, 1H);3.17 (s, 3H); 2.89 (s, 3H); 2.69 (t, J=7.6 Hz, 2H); 1.61 (5′, J=7.3 Hz,2H); 1.20 (6′, J=7.4 Hz, 2H); 0.79 (t, J=7.4 Hz, 3H).

Example 204-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-4-chlorobenzenesulfonate(7f)

20 g of (2-butyl-5-nitro-3-benzofuranyl)[4-hydroxyphenyl]methanon (VIII)was dissolved in 200 ml of dichloromethane and 8.95 g of triethylaminewas added under cooling at 20° C. 18.66 g of 4-chlorobenzenesulfonylchloride was added at 20° C. in 30 minutes under gentle cooling. Themixture was boiled for 5 hours. The cooled mixture was washed with 50 mlof sodium carbonate of 10% for 5 hours at 20° C. Phases were separated.The dichloromethane phase was evaporated.

Mass of residual oil: 32.93 g (108.7%). The yield is over 100% becauseof the solvent content of the obtained oil.

Purity (HPLC): 93.9%.

1H NMR(DMSO): 8.26 (m, 1H); 8.25 (m, 1H); 7.93 (d, J=8.6 Hz, 3H); 7.85(d, J=8.8 Hz, 2H); 7.76 (d, J=8.8 Hz, 2H); 7.29 (d, J=8.6 Hz, 2H); 2.73(t, J=7.7 Hz, 2H); 1.64(5′, J=7.4 Hz, 2H); 1.20 (6′, J=7.6 Hz, 2H); 0.79(t, J=7.4 Hz, 3H)

Example 214-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-4-chlorobenzenesulfonate(6f)

32.8 g of4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-4-chlorobenzene-sulfonate(7f) was dissolved in 330 ml of ethanol. 3.6 g of Pd/C of 10% was addedand the mixture was stirred at 75° C. under hydrogen pressure of 10 barsfor 3 hours. After cooling the catalyst was filtered off and the solventwas evaporated.

Mass of product: 30.6 g (99%).

Purity (HPLC): 97.8%.

1H NMR(DMSO): 7.93 (d, J=8.7 Hz, 2H); 7.77 (d, J=9.0 Hz, 2H); 7.75 (d,J=9.0 Hz, 2H); 7.27 (d, J=8.7 Hz, 1H); 7.24 (d, J=8.7 Hz, 2H); 6.60 (dd,J=2.3, 8.7 Hz, 1H); 6.55 (d, J=2.1 Hz, 1H); 5.05 (w, 2H); 2.61 (t, J=7.5Hz, 2H); 1.57 (5′, J=7.5 Hz, 2H); 1.18 (6′, J=7.3 Hz, 2H); 0.78 (t, 7.3Hz, 3H).

Example 224-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-chlorobenzene-sulfonate(2f)

30.6 g of4-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-4-chlorobenzene-sulfonate(6f) was dissolved in 300 ml of dichloromethane. The mixture was warmedto 30 to 35° C. and 5.5 g of pyridine was added at this temperature in 5minutes. 8 g of methanesulfonyl chloride was added at this temperaturein 30 minutes and the mixture was stirred at this temperature for 2hours. After cooling to 20° C. the mixture was washed with 2×160 ml ofwater, 1×160 ml of sodium bicarbonate of 5% and with 1×160 ml of water.The dichloromethane phase was almost evaporated (because of foaming theevaporation was not completed). 50 ml of ethanol was added and themixture was warmed until complete dissolution. After cooling to roomtemperature it was kept at this temperature overnight. It was filtered,washed with 10 ml of ethanol, dried.

Mass of product: 26.26 g (71.84%).

Purity (HPLC): 100%. M.p.: 121.2-123.3° C.

1H NMR(DMSO): 9.63 (s, 1H); 7.93 (d, J=8.6 Hz, 2H); 7.80 (d, J=8.6 Hz,2H); 7.77 (d, J=8.6 Hz, 2H); 7.63 (d, J=8.8 Hz, 1H); 7.30 (d, J=1.9 Hz,1H); 7.25 (d, J=8.6 Hz, 2H); 7.21 (dd, J=8.8, 2.0 Hz, 1H); 2.88 (s, 3H);2.70 (t, J=7.5 Hz, 2H); 1.62 (5′, J=7.5 Hz, 2H); 1.19 (6′, J=7.4 Hz,2H); 0.79 (t, J=7.5 Hz, 3H).

Example 234-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-4-methylbenzenesulfonate(7h)

20 g of (2-butyl-5-nitro-3-benzofuranyl)[4-hydroxyphenyl]methanon (VIII)was dissolved in 200 ml of dichloromethane. 8.95 g of triethylamine wasadded in 5 minutes at 20° C. 16.8 g of 4-methylbenzenesulfonyl chloridewas added in 30 minutes at 20° C. under cooling. The mixture was boiledfor 5 hours. After cooling the mixture was stirred with 70 ml of sodiumbicarbonate of 5% for 3.5 hours. Phase separation was performed. Thedichloromethane phase was evaporated.

Mass of product: 33.2 g (114.1%). The yield is over 100% because of thesolvent content of the obtained oil.

Purity (HPLC): 100%.

1H NMR(DMSO): 8.30 (dd, J=9.1, 2.4 Hz, 1H); 8.27 (d, J=2.9 Hz, 1H); 7.96(d, J=8.9 Hz, 1H); 7.86 (d, J=8.7 Hz, 2H); 7.82 (d, J=8.3 Hz, 2H); 7.52(d, J=8.3 HZ, 2H); 7.29 (d, J=8.6 Hz, 2H); 2.77 (t, J=7.5 Hz, 2H); 2.46(s, 3H); 1.68 (5′, J=7.3 Hz, 2H); 1.24 (6′, J=7.5 Hz, 2h); 0.83 (t,J=7.5 Hz, 2H).

Example 244-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-4-methylbenzenesulfonate(6h)

33.1 g of4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-4-methylbenzene-sulfonate(7h) was dissolved in 380 ml of ethanol. 3.9 g of Pd/C of 10% was addedand the mixture was stirred at 75° C. for 5 hours under hydrogenpressure of 10 bars. After cooling the catalyst was filtered off and thesolvent evaporated.

Mass of product: 28.8 g (100%).

Purity (HPLC): 100%.

1H NMR(DMSO): 7.83 (d, J=8.5 Hz, 2H); 7.77 (d, J=8.7 Hz, 2H); 7.53 (d,J=8.1 Hz, 2H); 7.30 (d, J=8.5 Hz, 1H); 7.24 (d, J=8.8 Hz, 2H); 6.62 (dd,J=2.2, 8.8 Hz, 1H); 6.58 (d, J=2.1 Hz, 1H); 4.99 (wide, 2H); 2.63 (t,J=7.5 Hz, 2H); 2.46 (s, 2H); 1.60 (5′, J=7.9 Hz, 2H); 1.21 (6′, J=7.5Hz, 2H); 0.81 (t, J=7.3 Hz, 3H).

Example 254-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-methylbenzene-sulfonate(2h)

30.8 g of4-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-4-methylbenzene-sulfonate(6h) was dissolved in 300 ml of dichloromethane. The mixture was warmedto 30 to 35° C. and 5.8 g of pyridine was added at this temperature in 5minutes. 8.4 g of methanesulfonyl chloride was added at this temperaturein 30 minutes and the mixture was stirred at this temperature for 2.5hours. After cooling to 20° C. the mixture was washed with 2×160 ml ofwater, 1×160 ml of sodium bicarbonate of 5% and 1×160 ml water. Thedichloromethane phase was evaporated.

Mass of residual material: 32.8 g (88.5%).

Purity (HPLC): 97.8%.

1H NMR(DMSO): 9.66 (s,1H); 7.82 (d, J=8.6 Hz, 4H); 7.66 (d, J=8.6 Hz,1H); 7.53 (d, J=8.0 Hz, 2H); 7.34 (d, J=2.1 Hz, 1H); 7.25 (m, 3H); 3.21(d, J=5.2 Hz, 1H); 2.91 (s, 3H); 2.73 (t, J=7.5 Hz, 2H); 2.45 (s, 3H);1.65 (m, J=7.3 Hz, 2H); 1.23 (m, 2H); 0.83 (t, J=7.4 Hz, 3H).

Example 26 4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-methanesulfonate (7i)

20 g of (2-butyl-5-nitro-3-benzofuranyl)[4-hydroxyphenyl]methanon (VIII)was dissolved in 200 ml of dichloromethane. 8.95 g of triethylamine wasadded in 5 minutes at 20° C. 10.1 g of methanesulfonyl chloride wasadded in 30 minutes at 20° C. under cooling. The mixture was boiled for12 hours. After cooling the mixture was stirred with 50 ml of sodiumbicarbonate of 5% for 2 hours and with 50 ml of water. The phases wereseparated. The dichlorometane phase was evaporated.

Mass of product: 24.86 g (100%).

Purity (HPLC): 100%.

1H NMR(DMSO): 8.32 (s, 1H); 8.31 (dd, J=9.0, 2.0 Hz, 1H); 7.98 (d, J=8.6Hz, 2+1H); 7.61 (d, J=8.5, 1.8 Hz, 1H); 3.53 (s, 3H); 2.83 (t, J=7.6 Hz,2H); 1.71 (5′, J=7.6 Hz, 2H); 1.27 (6′, J=7.5 Hz, 2H); 0.83 (t, J=7.4Hz, 3H).

Example 274-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-methanesulfonate(6i)

24.5 g of4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenyl-4-methanesulfonate(7i) was dissolved in 125 ml of ethanol. 8.6 g of Pd/C of 10% was addedand the mixture was stirred at 55° C. for 31 hours under hydrogenpressure of 10 bars. After cooling the catalyst was filtered off and thesolvent evaporated.

Mass of product: 22.1 g (99%).

Purity (HPLC): 96.0%.

1H NMR(DMSO): 7.92 (d, J=8.6 Hz, 2H); 7.62 (wide, 1H); 7.58 (d, J=8.6Hz, 2H); 7.08 (wide, 1H); 6.99 (wide, 1H); 3.52 (s, 3H); 2.75 (t, J=7.8Hz, 2H); 1.76 (5′, J=7.3 Hz, 2H); 1.25 (6′, J=7.5 Hz, 2H); 0.83 (t,J=7.5 Hz, 3H).

Example 284-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-methanesulfonate(2i)

12.4 g of 4-[(2-butyl-5-amino-1-benzofuran-3-yl)carbonyl]phenyl-methanesulfonate (6i) wasdissolved in 124 ml of dichloromethane. The mixture was warmed to 30 to35° C. and 2.8 g pyridine was added at this temperature in 5 minutes.4.0 g of methanesulfonyl chloride was added at this temperature in 30minutes and the mixture was stirred at 30 to 35° C. for 1 hour. Aftercooling to 20° C. the mixture was washed with 60 ml of hydrochloric acidsolution of 5%, with 60 ml of water, 60 ml of sodium bicarbonate of 5%and with 60 ml of water. The phases were evaporated.

Mass of product: 11.52 g (77.1%).

The product was crystallized in 80 ml of hot methanol.

Mass of pure product: 9.18 g.

Purity (HPLC): 100%. M.p.: 168.9-170.7° C.

1H NMR(DMSO): 9.62 (s,1H); 7.89 (d, J=8.7 Hz, 2H); 7.64 (d, J=8.8, 1H);7.53 (d, J=8.6, 2H); 7.29 (d, J=2.1, 1H); 7.21 (dd, J=8.8, 2.2 1H); 3.47(2.3H); 2.88 (s, 3H); 2.79 (t, J=7.5 Hz, 2H); 1.65 (5′, J=7.5 Hz, 2H);1.24 (6′, J=7.4Hz, 2H); 0.81 (t, J=7.3 Hz, 3H).

1-3. (canceled)
 4. A compound of formula (II), or a pharmaceuticallyacceptable salt thereof,

where L is a leaving group selected from the group consisting ofhalogen, alkylsulfonyloxy optionally substituted with one or morehalogen, and arylsulfonyloxy optionally substituted with halogen, alkyl,alkoxy or alkylsulfonylamino.
 5. A compound according to claim 4,selected from the group consisting of compounds:

6-17. (canceled)